Flaviviruses, such as West Nile virus and Dengue virus, present a significant threat to global health. West Nile virus causes a febrile illness that can lead to fatal meningitis or encephalitis across multiple species. West Nile virus can be carried by both birds and mosquitos, which has allowed its spread at an alarming pace worldwide. Similarly, four serotypes of Dengue virus can be transmitted through mosquito bites, and causes tens of millions of human cases of dengue annually, including 500,000 hospitalizations and 20,000 deaths, with an economic burden rivalling that of malaria.
Vaccines and antibody therapeutics are currently in development to prevent and treat flavivirus infection. However, evidence from dengue virus infections indicate that vaccination strategies for flaviviruses may not be as straightforward as other viruses. A first infection with one Dengue virus serotype induces protective immunity to the homologous serotype. However, there is no cross-protection against infection by a different serotype. Instead, pre-existing immunity is associated with increased risk of infection and illness due to antibody-dependent enhancement (ADE) of infection. In ADE, antibodies raised by prior flavivirus infection or passively transferred from mother to child cause an increased rate of infection and pathogenicity. Thus, conventional methods of antibody-based therapeutics or vaccines against flavivirus may exponentially increase incidence of flavivirus infection and illness.
Accordingly, there is an urgent need for therapeutics and methods for preventing flavivirus infection, and diseases and disorders related thereto, without increasing the risk of antibody-dependent enhancement of infection.